7-Phenylsulfonyl-tetrahydro-3-benzazepine derivatives as antipsychotic agents

ABSTRACT

The invention provides compounds of formula (I):  
                 
wherein 
         A and B represent the groups —(CH 2 ) m — and —(CH 2 ) n — respectively;    R 1  represents hydrogen or C 1-6 alkyl;    R 2  represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC 1-6 alkyl, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) p OC 3-6 cycloalkyl, —COC 1-6 alkyl, —SO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —S—C 1-6 alkyl, —CO 2 C 1-6 alkyl, —CO 2 NR 5 R 6 , —SO 2 NR 5 R 6 , —(CH 2 ) p NR 5 R 6 , —(CH 2 ) p NR 5 COR 6 , optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring;    R 3  represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC 1-6 alkyl, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) p OC 3-6 cycloalkyl, —COC 1-6 alkyl, —SO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —S—C 1-6 alkyl, —CO 2 C 1-6 alkyl, —CO 2 NR 7 R 8 , —SO 2 NR 7 R 8 , —(CH 2 ) p NR 7 R 8  or —(CH 2 ) p NR 7 COR 8 ;    R 4  represents hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkoxy, trifluoromethyl, trifluoromethoxy, halogen, —OSO 2 CF 3 , —(CH 2 ) p C 3-6 cycloalkyl, —(CH 2 ) q OC 1-6 alkyl or —(CH 2 ) p OC 3-6 cycloalkyl;    R 5  and R 6  each independently represent hydrogen, C 1-6 alkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo-substituted azacycloalkyl ring;    R 7  and R 8  each independently represent hydrogen or C 1-6 alkyl; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; q independently represents an integer selected from 1, 2 and 3; or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compounds 8-hydroxy-3-methyl-7-phenylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 8-hydroxy-7-4-(hydroxyphenyl)sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline and 7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride are excluded. The compounds are useful in therapy, in particular as antipsychotic agents.

This invention relates to novel compounds, pharmaceutical compositionscontaining them and their use in therapy, in particular as antipsychoticagents.

EP285287 describes 3-benzazepine compounds for use in treatinggastrointestinal motility disorders including the compounds8-hydroxy-3-methyl-7-phenylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepineand8-hydroxy-7-4-(hydroxyphenyl)sulfonyl-2.3,4,5-tetrahydro-1H-3benzazepine.

J. Med. Chem. 1999, 42, 118-134 and Biorg. Med. Chem. Lett, 1999, 9(3),481-486 describe 7-substituted-1,2,3,4-tetrahydroisoquinolines and theirrelative affinities toward phenylethanolamine N-methyltransferase,including the compound 7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinolineand its hydrochloride.

International patent applications WO98/06699, WO97/43262 and WO02/40471(SmithKline Beecham) disclose tetrahydroisoquinoline andtetrahydrobenzazepine derivatives which are selective D3 receptorantagonists and are said to be useful as antipsychotic agents. All ofthese derivatives possess a group other than hydrogen or alkyl attachedto the nitrogen atom of the tetrahydroisoquinoline ortetrahydrobenzazepine ring.

International patent application WO98/12180 (BASF) discloses hetaroylcyclohexanedione derivatives including tetrahydroisoquinolinederivatives that are said to be useful for controlling harmful plants.

International patent application WO02/46164 (AstraZeneca) disclosestetrahydroisoquinoline and isoindoline derivatives that areER-β-selective ligands and are said to be useful in the treatment orprophylaxis of Alzheimer's disease, anxiety disorders, depressivedisorders, osteoporosis, cardiovascular disease, rheumatoid arthritis orprostate cancer.

International patent application WO 01/85695 disclosestetrahydroisoquinoline analogues useful as growth hormone secretagogues.Such analogues are also said to be useful in the treatment of disordersincluding inter alia, obesity, schizophrenia, depression and Alzheimer'sdisease.

Japanese patent application JP2001/19676 (Takeda) describes thesynthesis of tetrahydrobenzazepine derivatives that are said to beuseful for increasing cAMP concentration in mammals and, in particular,for treating obesity.

We have now found a novel group of phenylsulfonyl compounds which areuseful particularly as antipsychotic agents.

According to the invention, there is provided a compound of formula (I):

wherein

-   -   A and B represent the groups —(CH₂)_(m)— and —(CH₂)_(n)—        respectively;    -   R¹ represents hydrogen or C₁₋₆alkyl;    -   R² represents hydrogen, halogen, hydroxy, cyano, nitro,        hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,        C₁₋₆alkoxy, C₁₋₆fluoroalkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl,        —(CH₂)_(p)OC₃₋₆cycloalkyl, —COC₁₋₆alkyl, —SO₂C₁₋₆alkyl,        —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁵R⁶, —SO₂NR⁵R⁶,        —(CH₂)_(p)NR⁵R⁶, —(CH₂)_(p)NR⁵COR⁶, optionally substituted aryl        ring, optionally substituted heteroaryl ring or optionally        substituted heterocyclyl ring;    -   R³ represents hydrogen, halogen, hydroxy, cyano, nitro,        hydroxyC₁₋₆alkyl, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,        C₁₋₆alkoxy, C₁₋₆fluoroalkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl,        —(CH₂)_(p)OC₃₋₆cycloalkyl, —COC₁₋₆alkyl, —SO₂C₁₋₆alkyl,        —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸, —SO₂NR⁷R⁸,        —(CH₂)_(p)NR⁷R⁸ or —(CH₂)_(p)NR⁷COR⁸;    -   R⁴ represents hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,        C₁₋₆fluoroalkoxy, trifluoromethyl, trifluoromethoxy, halogen,        —OSO₂CF₃, —(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(q)OC₁₋₆alkyl or        —(CH₂)_(p)OC₃₋₆cycloalkyl;    -   R⁵ and R⁶ each independently represent hydrogen, C₁₋₆alkyl or,        together with the nitrogen or other atoms to which they are        attached, form an azacycloalkyl ring or an oxo-substituted        azacycloalkyl ring;    -   R⁷ and R⁸ each independently represent hydrogen or C₁₋₆alkyl;    -   m and n independently represent an integer selected from 1 and        2;    -   p independently represents an integer selected from 0, 1, 2 and        3;    -   q independently represents an integer selected from 1, 2 and 3;    -   or a pharmaceutically acceptable salt or solvate thereof,    -   with the proviso that the compounds        8-hydroxy-3-methyl-7-phenylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine,        8-hydroxy-7-4-(hydroxyphenyl)sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine,        7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline and        7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride        are excluded.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

As used herein, the term “alkyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms. Forexample, C₁₋₆alkyl means a straight or branched alkyl containing atleast 1, and at most 6, carbon atoms. Examples of “alkyl” as used hereininclude, but are not limited to, methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl.

As used herein, the term “alkoxy” refers to a straight or branchedalkoxy group containing the specified number of carbon atoms. Forexample, C₁₋₆alkoxy means a straight or branched alkoxy group containingat least 1, and at most 6, carbon atoms. Examples of “alkoxy” as usedherein include, but are not limited to, methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy,2,2,2-trifluoroethoxy, 2,2-dimethylprop-1-oxy, —O—CH₂-c-propyl, pentoxyor hexyloxy.

As used herein, the term “C₁₋₆fluoroalkoxy” refers to a straight orbranched alkoxy group containing the specified number of carbon atomswherein any of the carbon atoms may be substituted by one or morefluorine atoms. Examples of “C₁₋₆fluoroalkoxy” as used herein include,but are not limited to, 2,2,2-trifluoroethoxy.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring containing the specified number of carbon atoms. Forexample, C₃₋₇-cycloalkyl means a non-aromatic ring containing at leastthree, and at most seven, ring carbon atoms. Examples of “cycloalkyl” asused herein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. A C₆₋₇cycloalkyl group ispreferred.

As used herein, the term “halogen” refers to the elements fluorine,chlorine, bromine and iodine. Preferred halogens are fluorine, chlorineand bromine.

As used herein, the term “aryl” refers to a phenyl or a naphthyl ring.

As used herein, the term “heteroaryl” refers to a 5- or 6-memberedheterocyclic aromatic ring or a fused bicyclic heteroaromatic ringsystem.

As used herein, the term “heterocyclyl” refers to a 3- to 7-memberedmonocyclic saturated ring containing at least one heteroatomindependently selected from oxygen, nitrogen and sulfur. Examples ofsuitable heterocyclic rings include, but are not limited to, piperidineand morpholine.

As used herein, the term “5- or 6-membered heterocyclic aromatic ring”refers to a monocyclic unsaturated ring containing at least oneheteroatom independently selected from oxygen, nitrogen and sulfur.Examples of suitable 5- and 6-membered heterocyclic aromatic ringsinclude, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl,triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl andisoxazolyl.

As used herein, the term “fused bicyclic heteroaromatic ring system”refers to a ring system comprising one six-membered unsaturated ring andone 5- or 6-membered unsaturated ring fused together, the ring systemcontaining at least one heteroatom independently selected from oxygen,nitrogen and sulfur. Examples of suitable fused bicyclic heteroaromaticring systems include, but are not limited to, indolyl, benzofuranyl,quinolyl and benzothienyl.

As used herein, the term “azacycloalkyl ring” refers to a 4- to7-membered monocyclic saturated ring containing one nitrogen atom.Examples of suitable azacycloalkyl rings are azetidine, pyrrolidine,piperidine and azepine.

As used herein, the term “oxo-substituted azacycloalkyl ring” refers toan azacycloalkyl ring as defined above substituted by one oxo group.Examples of suitable oxo-substituted azacycloalkyl rings include, butare not limited to, azetidinone, pyrrolidinone, piperidinone andazepinone.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Most preferably the solvent used is water andthe solvate may also be referred to as a hydrate.

It will be appreciated that for use in medicine the salts of formula (I)should be physiologically acceptable. Suitable physiologicallyacceptable salts will be apparent to those skilled in the art andinclude for example acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, malic, mandelic, acetic, fumaric,glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic,p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Othernon-physiologically acceptable salts e.g. oxalates, may be used, forexample in the isolation of compounds of formula (I) and are includedwithin the scope of this invention. Also included within the scope ofthe invention are solvates and hydrates of the compounds of formula (I).

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms thereof.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The presentinvention also covers the individual isomers of the compoundsrepresented by formula (I) as mixtures with isomers thereof in which oneor more chiral centres are inverted. Likewise, it is understood thatcompounds of formula (I) may exist in tautomeric forms other than thatshown in the formula and these are also included within the scope of thepresent invention.

The groups R², R³ and R⁴ may be located on any position on theirrespective phenyl rings. When R² represents an optionally substitutedaryl ring, an optionally substituted heteroaryl ring, or an optionallysubstituted heterocycdyl ring, the optional substituents may be selectedfrom C₁₋₆alkyl, C₁₋₆alkoxy, halogen, trifluoromethyl, trifluoromethoxy,cyano and —S—C₁₋₆alkyl.

Preferably, R¹ represents hydrogen or C₁₋₄alkyl. More preferably, R¹represents hydrogen, methyl, ethyl, n-propyl or isopropyl. Even morepreferably, R¹ represents hydrogen, methyl, ethyl or isopropyl.

Preferably, R² represents hydrogen, halogen, C₁₋₆alkyl or C₁₋₆alkoxy.More preferably, R² represents hydrogen, halogen, C₁₋₄alkyl orC₁₋₄alkoxy. Even more preferably, R² represents hydrogen, methoxy orbromo.

In a first embodiment of the invention, the R² group is located at thepara-position relative to the group B i.e. a compound of formula (IA)

or a pharmaceutically acceptable salt or solvate thereof wherein groupsA, B and R¹ to R⁴ have any of the meanings as given hereinbefore.

When R² is located in the para-positim i.e. compounds of formula (IA),R² is preferably hydrogen or methoxy.

For compounds of the formulae (I) or (IA), preferably, when R²represents an optionally substituted aryl ring, an optionallysubstituted heteroaryl ring, or an optionally substituted heterocyclylring, the optional substituents are independently selected fromchlorine, fluorine, bromine, methyl, ethyl, t-butyl, methoxy,trifluoromethyl, trifluoromethoxy, cyano, —S-methyl and —NR⁵R⁶ whereinR⁵ and R⁶ are as hereinbefore described.

For compounds of the formulae (I) or (IA), preferably, R³ representshydrogen, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy. More preferably, R³represents hydrogen, methyl or methoxy. Even more preferably, R³represents hydrogen, methyl or methoxy.

In another embodiment of the invention, the R³ group is located at theortho-position relative to the sulfone group i.e. a compound of formula(IB)

or a pharmaceutically acceptable salt or solvate thereof wherein groupsA, B and R¹ to R⁴ have any of the meanings as given hereinbefore.

When R³ is located in the ortho-position i.e. compounds of formula (IB),R³ is preferably hydrogen, methyl or methoxy.

For compounds of the formulae (I), (IA) or (IB), preferably, R⁴represents hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄fluoroalkoxy,trifluoromethyl, trifluoromethoxy, halogen or —OSO₂CF₃. More preferably,R⁴ represents C₁₋₄alkyl or C₁₋₄alkoxy. More preferably, R⁴ representsisopropyl, n-butyl, t-butyl, ethoxy, propoxy, isopropoxy,trifluoromethoxy, —OSO₂CF₃, 2,2,2-trifluoroethoxy,2,2-dimethylprop-1-oxy, —OCH₂-c-propyl, or pentoxy.

In another embodiment of the invention, the R⁴ group is located at themeta-position relative to the sulfone group i.e. a compound of formula(IC)

or a pharmaceutically acceptable salt or solvate thereof wherein groupsA, B and R¹ to R⁴ have any of the meanings as given hereinbefore.

When R⁴ is located in the meta-position i.e. compounds of formula (IC),R⁴ is preferably C₁₋₄alkyl or C₁₋₄alkoxy.

In another embodiment of the invention, the R⁴ group is located at thepara-position relative to the sulfone group i.e. a compound of formula(ID)

or a pharmaceutically acceptable salt or solvate thereof wherein groupsA, B and R¹ to R⁴ have any of the meanings as given hereinbefore.

When R⁴ is located in the para-position i.e. compounds of formula (ID),R⁴ is preferably C₁₋₄alkyl or C₁₋₄alkoxy. More preferably, R⁴ representsisopropyl, n-butyl, t-butyl, ethoxy, propoxy, isopropoxy,trifluoromethoxy, —OSO₂CF₃, 2,2,2-trifluoroethoxy,2,2-dimethylprop-1-oxy, —OCH₂-c-propyl, or pentoxy.

In another embodiment of the invention, the R³ group is located at theortho-position relative to the sulfone group and the R⁴ group is locatedat the para-position relative to the sulfone group i.e. a compound offormula (IE)

or a pharmaceutically acceptable salt or solvate thereof wherein groupsA, B and R¹ to R⁴ have any of the meanings as given hereinbefore.

For compounds of the formulae (I), (IA), (IB), (IC), (ID) or (IE),preferably, R⁵ and R⁶ independently represent hydrogen or C₁₋₄alkyl.More preferably, R⁵ and R⁶ independently represent hydrogen or methyl.

For compounds of the formulae (I), (IA), (IB), (IC), (ID) or (IE),preferably, R⁷ and R⁸ independently represent hydrogen or C₁₋₄alkyl.More preferably, R⁷ and R⁸ independently represent hydrogen or methyl.

For compounds of the formula (I), (IA), (IB), (IC), (ID) or (IE),preferably, p represents 0. In another embodiment of the invention, m is1 and n is 1 and the invention is a compound of formula (IF):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 1 and theinvention is a compound of formula (IG):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 1 and n is 2 and theinvention is a compound of formula (IH):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 2 and theinvention is a compound of formula (IJ):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 2, the R² groupis located at the para-position relative to the group B, the R³ group islocated at the ortho-position relative to the sulfone group, the R⁴group is located at the meta-position relative to the sulfone group andthe invention is a compound of formula (IK):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 2, the R² groupis located at the para-position relative to the group B, the R³ group islocated at the ortho-position relative to the sulfone group, the R⁴group is located at the para-position relative to the sulfone group andthe invention is a compound of formula (IL):

or a pharmaceutically acceptable salt or solvate thereof wherein groupsR¹ to R⁴ have any of the meanings as given hereinbefore.

Particular compounds according to the invention indude thoseincorporated in Tables 1 and 2 and those specifically exemplified andnamed hereinafter including, without limitation:

-   -   7-(4-n-butylphenylsulfonyl)-1,2,3,5-tetrahydro-3-benzazepine;        and    -   7-(4-n-butylphenylsulfonyl)-3-methyl-1,2,3,5-tetrahydro-3-benzazepine.

The compounds of the present invention may be in the form of their freebase or physiologically acceptable salts thereof, particularly themonohydrochloride or monomesylate salts or pharmaceutically acceptablederivatives thereof.

The present invention also provides a general process (A) for preparingcompounds of formula (I) which process comprises:reacting a compound of formula (II)

with a compound of formula (III)

wherein L is a leaving group, such as fluoro, chloro, alkoxy or aryloxy,M is a metal, such as lithium or magnesium, R^(1′)-R^(4′) represent R¹to R⁴ as hereinbefore defined or are groups that may be readilyconvertible to R¹ to R⁴, and A and B are as hereinbefore defined.

This general method (A) can be conveniently performed by mixing the twocomponents at preferably −70° C. to room temperature in a suitablesolvent such as tetrahydrofuran or ether for 10 minutes to 18 hours.Removal of certain R^(1,) protecting groups e.g. trifluoroacetyl, canalso take place simultaneously during this process.

The present invention also provides a general process (B) for preparingcompounds of formula (I), which process comprises:reacting a compound of formula (IV)

with an alkyl boronic acid of formula (V)

wherein X is a leaving group, such as bromo, iodo, chloro, triflate orN₂ ⁺. A and B are as hereinbefore defined and R^(1′)-R^(4′) represent R¹to R⁴ as hereinbefore defined or are groups that may be readilyconvertible to R¹ to R⁴. This general method (B) can be convenientlyperformed by mixing the two components in a suitable solvent such astoluene or ethanol containing aqueous sodium carbonate and a catalyticamount of Pd(PPh₃)₄ at room temperature or reflux under argon.

The present invention also provides a general process (C) for preparingcompounds of formula (I) which process comprises:reacting a compound of formula (VI)

with a compound of formula (VII)

wherein L is a leaving group, such as fluoro, chloro, alkoxy or aryloxy,M is a metal, such as lithium or magnesium, A and B are as hereinbeforedefined and R^(1′)-R^(4′) represent R¹ to R⁴ as hereinbefore defined orare groups that may be readily convertible to R¹ to R⁴. This generalmethod (C) can be conveniently performed by mixing the two components atpreferably −70° C. to room temperature in a suitable solvent such astetrahydrofuran or ether for 10 minutes to 18 hours.

The present invention also provides a general process (D) for preparingcompounds of formula (I) which process comprises:reacting a reagent of formula (VIII)

with a compound of formula (IX)

wherein L is a leaving group, such as fluoro, chloro or triflate, A andB are as hereinbefore defined and R^(1′)-R^(4′) represent R¹ to R⁴ ashereinbefore defined or are groups that may be readily convertible to R¹to R⁴. This general method (D) can be conveniently performed by mixingthe two components in a suitable solvent such as dimethylformamide inthe presence of copper iodide at elevated temperature e.g. 120° C.

The present invention also provides a general process (E) for preparingcompounds of formula (I) which process comprises:reacting a reagent of formula (X)

with a compound of formula (IX)

followed by the oxidation of the resultant sulfide, by for example,meta-chloroperbenzoic acid, wherein L is a leaving group, such asfluoro, chloro, triflate or N₂ ⁺, A and B are as hereinbefore definedand R^(1′)-R^(4′) represent R¹ to R⁴ as hereinbefore defined or aregroups that may be readily convertible to R¹ to R⁴. This general method(E) can be conveniently performed by mixing the two components in asuitable solvent such as dimethylformamide, optionally at elevatedtemperature e.g. 120° C.

Interconversion of one of the R^(1′) to R^(5′) groups to thecorresponding R¹ to R⁴ groups typically arises when one compound offormula (I) is used as the immediate precursor of another compound offormula (I), or when it is easier to introduce a more complex orreactive substituent at the end of a synthetic sequence.

For example, conversion of R^(1′) from a t-butoxycarbonyl (BOC) group tohydrogen is conducted by the treatment of the N-BOC protected compoundwith hydrogen chloride in ethanol or dioxan at room temperature.

Conversion of R^(1′) from hydrogen to an alkyl group is conducted by thetreatment of the NH compound with the appropriate aldehyde indichloroethane in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, or by the treatment of the NH compound with theappropriate alkyl halide, such as iodomethane, under standard alkylationconditions (potassium carbonate in DMF at 60° C.).

Compounds of formula (II) are known in the literature or may be preparedby known processes, for example, chlorosulfonation of the aromatic ringusing chlorosulfonic acid. Conversion to the suffonyl fluoride can beachieved, if required, by reaction with potassium fluoride inacetonitrile at room temperature. Suitable examples of an R^(1′)protecting group are trifluoroacetyl or the t-butoxycarbonyl (BOC)group.

Compounds of formula (III) are commercially available or may be preparedby established procedures, for example lithiation of the correspondingbromobenzene in tetrahydrofuran at low temperature, with for examplet-butyl lithium.

Compounds of formula (IV) may be prepared using a similar process togeneral process A.

Compounds of formula (V) are commercially available, or may be preparedby lithiation of the corresponding bromo aromatic compound, followed byquenching with tri-isopropyl borate then hydrolysis.

Compounds of formula (VI) may be prepared by metal halogen exchangeusing the corresponding bromo analogue as starting material and t-butyllithium at low temperature. Compounds of formula (VII) are commerciallyavailable or may be prepared by chlorosulfonylation of the aromaticring. Conversion to the sulfonyl fluoride can be achieved, if required,by reaction with potassium fluoride in acetonitrile at room temperature.

Compounds of formula (VIII) may be prepared by reduction of thecorresponding sulfonyl chloride, using for example sodium bisulphite andsodium bicarbonate in tetrahydrofuran/water. Deprotonation of thesulfinic add can be achieved by treatment with base, e.g. sodiumhydride.

Compounds of formula (IX) are commercially available or may be preparedusing standard literature methodology.

Compounds of formula (X) may be prepared by reduction of compounds offormula (II) using for example lithium aluminium hydride intetrahydrofuran. Deprotonaton of the thiol can be achieved by treatmentwith base, e.g. sodium hydride.

Compounds of formula (I) have antagonist affinity for the serotonin5-HT_(2C), 5-HT_(2A) and 5-HT₆ receptors. These properties may give riseto anti-psychotic activity (e.g. improved effects on cognitivedysfunction) activity with reduced extrapyramidal side effects (eps),and/or anxiolytic/antidepressant activity. These could include, but arenot limited to, attenuation of cognitive symptoms via 5-HT₆ receptorblockade (see Reavill, C. and Rogers, D. C., 2001, Investigational Drugs2, 104-109), and reduced anxiety (see for example Kennett et al.,Neuropharmacology 1997 April-May; 36 (4-5): 609-20), protection againstEPS (Reavill et al., Brit. J. Pharmacol., 1999; 126: 572-574) andantidepressant activity (Bristow et al., Neuropharmacology 39:2000;1222-1236) via 5-HT_(2C) receptor blockade.

Certain compounds of formula (I) have also been found to exhibitaffinity for dopamine receptors, in particular the D₃ and D₂ receptors,and are useful in the treatment of disease states which requiremodulation of such receptors, such as psychotic conditions. Many of thecompounds of formula (I) have also been found to have greater affinityfor dopamine D₃ than for D₂ receptors. The therapeutic effect ofcurrently available antipsychotic agents (neuroleptics) is generallybelieved to be exerted via blockade of D₂ receptors; however thismechanism is also thought to be responsible for undesirable epsassociated with many neuroleptic agents. Without wishing to be bound bytheory, it has been suggested that blockade of the dopamine D₃ receptormay give rise to beneficial antipsychotic activity without significanteps (see for example Sokoloff et al, Nature, 1990; 347: 146-151; andSchwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314,1993).

Compounds of formula (I) may also exhibit affinity for other receptorsnot mentioned above, resulting in beneficial antipyschotic activity.

The compounds of formula (I) are of use as antipsychotic agents forexample in the treatment of schizophrenia, schizoaffective disorders,schizophreniform diseases, psychotic depression, mania, acute mania,paranoid and delusional disorders. Furthermore, they may have utility asadjunct therapy in Parkinsons Disease, particularly with compounds suchas L-DOPA and possibly dopaminergic agonists, to reduce the side effectsexperienced with these treatments on long term use (e.g. see Schwartz etal., Brain Res. Reviews, 1998, 26, 236-242). From the localisation of D₃receptors, it could also be envisaged that the compounds could also haveutility for the treatment of substance abuse where it has been suggestedthat D3 receptors are involved (e.g. see Levant, 1997, Pharmacol. Rev.,49, 231-252). Examples of such substance abuse include alcohol, cocaine,heroin and nicotine abuse. Other conditions which may be treated by thecompounds include dyskinetic disorders such as Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias; depression;anxiety; agitation; tension; social or emotional withdrawal in psychoticpatients; cognitive impairment including memory disorders such asAlzheimer's disease; psychotic states associated with neurodegenerativedisorders, e.g. Alzheimer's disease; eating disorders; obesity; sexualdysfunction; sleep disorders; emesis; movement disorders;obsessive-compulsive disorders; amnesia; aggression; autism; vertigo;dementia; circadian rhythm disorders; and gastric motility disorderse.g. IBS.

Therefore, the invention provides a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof for use in therapy.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in thetreatment of a condition which requires modulation of a dopaminereceptor.

The invention also provides a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt or solvate thereof foruse in the treatment of psychotic disorders, schizophrenia, Parkinsonsdisease, substance abuse, dyskinetic disorders, depression, bipolardisorder, anxiety, cognitive impairment, eating disorders, obesity,sexual dysfunction, sleep disorders, emesis, movement disorders,obsessive-compulsive disorders, amnesia, aggression, autism, vertigo,dementia, circadian rhythm disorders and gastric motility disorders.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for the treatment of acondition which requires modulation of a dopamine receptor.

The invention also provides the use of a compound of formula (I) ashereinbefore described or a pharmaceutically acceptable salt or solvatethereof in the manufacture of a medicament for the treatment ofpsychotic disorders, schizophrenia, Parkinsons disease, substance abuse,dyskinetic disorders, depression, bipolar disorder, anxiety, cognitiveimpairment, eating disorders, obesity, sexual dysfunction, sleepdisorders, emesis, movement disorders, obsessive-compulsive disorders,amnesia, aggression, autism, vertigo, dementia, circadian rhythmdisorders and gastric motility disorders.

The invention also provides a method of treating a condition whichrequires modulation of a dopamine receptor, which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I) as hereinbefore described or a pharmaceuticallyacceptable salt or solvate thereof.

The invention also provides a method of treating psychotic disorders,schizophrenia, Parkinsons disease, substance abuse, dyskineticdisorders, depression, bipolar disorder, anxiety, cognitive impairment,eating disorders, obesity, sexual dysfunction, sleep disorders, emesis,movement disorders, obsessive-compulsive disorders, amnesia, aggression,autism, vertigo, dementia, circadian rhythm disorders and gastricmotility disorders which comprises administering to a mammal in needthereof an effective amount of a compound of formula (I) as hereinbeforedescribed or a pharmaceutically acceptable salt or solvate thereof.

A preferred use for dopamine antagonists according to the presentinvention is in the treatment of psychotic disorders, schizophrenia,Parkinsons disease, substance abuse, dyskinetic disorders, depression,bipolar disorder, anxiety and cognitive impairment. “Treatment” includesprophylaxis, where this is appropriate for the relevant condition(s).

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, differentantidepressant agents such as 5HT₃ antagonists, serotonin agonists, NK-1antagonists, selective serotonin reuptake inhibitors (SSRI),noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants,dopaminergic antidepressants, H₃ antagonists, 5HT_(1A) antagonists,5HT_(1B) antagonists, 5HT_(1D) antagonists, D₁ agonists, M₁ agonistsand/or anticonvulsant agents.

Suitable 5HT₃ antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention indude imipramine, amitriptiline,chlomipranine and nortriptiline. Suitable dopaminergic antidepressantswhich may be used in combination with a compound of the invention indudebupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of thecompounds of the inventions include for example divalproex,carbamazepine and diazepam.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations), separately or sequentially.

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of formula (I) as hereinbeforedescribed or a pharmaceutically (i.e. physiologically) acceptable saltthereof and a pharmaceutically (i.e. physiologically) acceptablecarrier. The pharmaceutical composition can be for use in the treatmentof any of the conditions described herein.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral (e.g. intravenous), buccal,sublingual, nasal, rectal or transdermal administration and thepharmaceutical compositions adapted accordingly.

The compounds of formula (I) as hereinbefore described and theirpharmaceutically acceptable salts which are active when given orally canbe formulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochloro-hydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration indude ointments,gels and patches. Preferably the composition is in unit dose form suchas a tablet, capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, preferably between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof calculated as the free base, the compound being administered 1to 4 times per day. Suitably the compounds will be administered for aperiod of continuous therapy, for example for a week or more.

No toxicological effects are indicated/expected when a compound of theinvention is administered in the above mentioned dosage range.

Biological Test Methods

Binding Experiments on Cloned Dopamine (e.g. D2 and D3) Receptors

The ability of the compounds to bind selectively to human D2/D3 dopaminereceptors can be demonstrated by measuring their binding to clonedreceptors. The inhibition constants (K_(i)) of test compounds fordisplacement of [¹²⁵l]-lodosulpride binding to human D2/D3 receptorsexpressed in CHO cells were determined as follows. The cell lines wereshown to be free from bacterial, fungal and mycoplasmal contaminants,and stocks of each were stored frozen in liquid nitrogen. Cultures weregrown as monolayers or in suspension in standard cell culture media.Cells were recovered by scraping (from monolayers) or by centrifugation(from suspension cultures), and were washed two or three times bysuspension in phosphate buffered saline followed by collection bycentrifugation. Cell pellets were stored frozen at −80° C. Crude cellmembranes were prepared by homogenisation followed by high-speedcentrifugation, and characterisation of cloned receptors achieved byradioligand binding.

Preparation of CHO cell membranes: Cell pellets were gently thawed atroom temperature, and resuspended in about 20 volumes of ice-coldExtraction buffer, 5 mM EDTA, 50 mM Trizma pre-set crystals (pH7.4@37°C.), 1 mM MgCl₂, 5 mM KCl and 120 mM NaCl. The suspension washomogenised using an Ultra-Turrax at full speed for 15 seconds. Thehomogenate was centrifuged at 18,000 r.p.m. for 15 min at 4° C. in aSorvall RC5C centrifuge. Supernatant was discarded, and homogenatere-suspended in extraction buffer then centrifugation was repeated. Thefinal pellet was resuspended in 50 mM Trizma pre-set crystals (pH7.4@37° C.) and stored in 1 ml aliquot tubes at −80° C. (D2=3.0E+08cells, D3=7.0E+07 cells and D4=1.0E+08 cells). The protein content wasdetermined using a BCA protocol and bovine serum albumin as a standard(Smith, P. K., et al., Measurement of protein using bicinchoninic acid.Anal. Biochem. 150, 76-85 (1985)).

Binding experiments: Crude D2/D3 cell membranes were incubated with 0.03nM [¹²⁵l]-lodosulpride (˜2000 Ci/mmol; Amersham, U. K., and the testcompound in a buffer containing 50 mM Trizma pre-set crystals (pH7.4@37° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.3% (w/v)bovine serum albumin. The total volume is 0.2 ml and incubated in awater bath at 37° C. for 40 minutes. Following incubation, samples werefiltered onto GF/B Unifilters using a Canberra Packard Filtermate, andwashed four times with ice-cold 50 mM Trizma pre-set crystals (pH7.4@37° C.). The radioactivity on the filters was measured using aCanberra Packard Topcount Scintillation counter. Non-specific bindingwas defined with 10 μM SKF-102161 (YM-09151). For competition curves, 10serial log concentrations of competing cold drug were used (Dilutionrange: 10 μM-10 pM). Competition curves were analysed using Inflexion,an iterative curve fitting programme in Excel. Results were expressed aspK_(i) values where pK_(i)=−log10[Ki].

The exemplified compounds have pK_(i) values within the range of 5.8-8.2at the dopamine D₃ receptor.

The exemplified compounds have pK_(i) values within the range of 5.3-7.7at the dopamine D₂ receptor.

Binding Experiments on Cloned 5-HT₆ Receptors

Compounds can be tested following the procedures outlined in WO98/27081.

The exemplified compounds have pK_(i) values within the range of 7.2-8.9at the serotonin 5-HT₆ receptor.

Binding Experiments on Cloned 5-HT_(2A) and 5-HT_(2C) Receptors

Compounds can be tested following the procedures outlined in WO94/04533.

The exemplified compounds have pK_(i) values within the range of 7.1-9.7at the serotonin 5-HT_(2C) receptor and of 7.0-10.0 at the serotonin5-HT_(2A) receptor.

The invention is further illustrated by the following non-limitingexamples:

Description 13-Trifluoroacetyl-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonyl fluoride(D1)

a) 3-Trifluoroacetyl-1,2,4,5-tetrahydro-3benzazepine-7-sulfonyl chloride

A solution of 3-trifluoroacetyl-1,2,4,5-tetrahydro-3-benzazepine (20 g,80 mmol) in dichloromethane (50 ml) was added dropwise to a solution ofchlorosulfonic acid (33 ml, 240 mmol) in more dichloromethane (200 ml)at 0° C. The resulting solution was stirred for 18 h without coolingthen poured onto ice (250 g). The resulting organic layer was washedwith brine (100 ml), dried (MgSO₄), and evaporated to give the subtitlecompound as a white solid (23 g).

b) 3-Trifluoroacetyl-1,2,4,5tetrahydro-3-benzazepine-7-sulfonyl fluoride

A mixture of3-trifluoroacetyl-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonyl chloride(23 g, 67 mmol), potassium fluoride (12 g, 200mmol), 18-crown6 (0.1 g),and acetonitrile (100 ml) was stirred overnight. Water (200 ml) andethyl acetate (200 ml) were added and the organic layer was washed withbrine (100 ml), dried (MgSO₄), and evaporated to give the title compoundas a white solid (21 g). ¹H NMR δ (d₆-DMSO) 3.2 (4H, m), 3.7 (4H, m),7.6 (1H, m), and 8.0 (2H, m).

Description 23-Trifluoroacetyl-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonylfluoride (D2)

a) 3-Trifluoroacetyl-8-methoxy-1,2,4,5-tetrahydro3-benzazepine

To a mixture of 8-methoxy-1,2,4,5-tetrahydro-3-benzazepine hydrochloride(5.1 g, 25 mmol), triethylamine (8.4 ml, 60 mmol), and dichloromethane(100 ml) at 0° C., was added dropwise trifluoroacetic anhydride (3.5 ml,26 mmol). The solution was stirred for 2 h without cooling then washedwith saturated aqueous sodium hydrogen carbonate(100 ml), and water (100ml). dried (MgSO₄), and evaporated to give the title compound as a whitesolid (5.5 g).

b)3-Trifluoroacetyl-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonylchloride

Prepared from3-trifluoroacetyl-8-methoxy-1,2,4,5tetrahydro-3-benzazepine using themethod of Description 1(a); yield 85%.

c)3-Trifluoroacetyl-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonylfluoride

Prepared from3-trifluoroacetyl-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonylchloride using the method of Description 1(b); yield 80%.

¹H NMR δ (d₆-DMSO) 3.1 (4H, m), 3.7 (4H, m), 4.0 (3H, s), 7.3 (1H, 2s,rotamers), and 7.8 (1H, 2s, rotamers).

EXAMPLE 1 7-(4-n-Butylphenylsulfonyl)-1,2,4,5-tetrahydro-3-benzazepine(E1)

A solution of 4-n-butylbromobenzene (4.7 g, 22 mmol) in THF (35 ml) at−70° C. was treated with tert-butyllithium (25 ml, 1.7 M in pentane, 42mmol). After 20 min at −70° C., a solution of D1 (2.7 g, 7.5 mmol inmore THF (10 ml) was added, and after a further 30 min stirring withoutcooling, water (100 ml) and ethyl acetate (100 ml) were added. Theorganic layer was washed with brine (100 ml), dried (MgSO₄), andevaporated. Chromatography on silica, eluting with 0 to 15% methanol indichloromethane containing 0.1 M ammonia, gave the title compound,isolated as the hydrochloride salt from ether (1.6 g). MH⁺ 344. ¹H NMR δ(d₆-DMSO) 0.9 (3H,t J=7 Hz), 1.3 (2H, m), 1.5 (2H, m), 2.6 (2H, t, J=8Hz), 3.2 (8H, m), 7.4 (3H, m), 7.8 (4H, m), and 9.3 (2H, bs).

EXAMPLE 27-(4-n-Butylphenylsulfonyl)-3-methyl-1,2,4,5-tetrahydro-3-benzazepine(E2)

A mixture of E1 hydrochloride salt (1.6 g, 4.7 mmol), sodiumtriacetoxyborohydride (5.0 g), aqueous formaldehyde (5.0 ml, 37%), and1,2-dichloroethane (100 ml) was stirred for 18 h then diluted withdichloromethane (50 ml) and washed with saturated aqueous sodiumhydrogen carbonate (100 ml), dried (MgSO₄), and evaporated to give thetitle compound isolated as the hydrochloride salt from ether (1.3 g).MH⁺ 358. ¹H NMR δ (d₆-DMSO) 0.9 (3H, t J=7 Hz), 1.3 (2H, m), 1.5 (2H,m), 2.6 (2H, t, J=8 Hz), 2.8 (3H, d, J=5 Hz), 2.9-3.6 (8H, m), 7.4 (3H,m), 7.8 (4H, m), and 11.1 (1H, bs).

Examples 3-47 were prepared using analogous procedures to Examples 1 and2. Products were isolated as either the free bases or hydrochloridesalts. All ¹H NMR are consistent with the structures shown.

All of the compounds listed below in Table 1 relate to compounds offormula (I), (IA), (IB), (ID), (IE), (IJ) and (IL) wherein m and n bothare 2: TABLE 1

Example R¹ R² R³ R⁴ MH⁺ 1 H H H nBu 344 2 Me H H nBu 358 3 H OMe H nBu374 4 Me OMe H nBu 388 5 H H H tBu 344 6 Me H H tBu 358 7 H H H iPr 3308 Me H H iPr 344 9 Et OMe H nBu 402 10 Me OMe H iPr 374 11 H OMe H iPr360 12 H OMe H tBu 374 13 Me OMe H tBu 388 14 H OH H nBu 360 28 H H HOCF₃ 372 29 Me H H OCF₃ 386 30 H H H OnPr 346 31 H H H OSO₂CF₃ 436 32 MeH H OnPr 360 33 H OMe H OCF₃ 402 34 Me OMe H OCF₃ 416 35 H OMe H OnPr376 36 Me OMe H OnPr 390 48 Me OMe H OEt 376 49 Me OMe H OCH₂CF₃ 430 50Me OMe H O-iPr 390 51 Me OMe H OCH₂-tBu 418 52 Me OMe H OCH₂-c-propyl402 53 Me OMe H O-c-pentyl 416 54 Me OMe Me OnPr 404

All of the compounds listed below in Table 2 relate to compounds offormula (I), (IA), (IB), (IC), (IJ) and (IK) wherein m and n both are 2:TABLE 2

Example R¹ R² R³ R⁴ MH⁺ 15 H H H nBu 344 16 Me H H nBu 358 17 H OMe HnBu 374 18 Me OMe H nBu 388 19 iPr OMe H nBu 416 20 H H H iPr 330 21 MeH H iPr 344 22 H OMe H iPr 360 23 Me OMe H iPr 374 24 H H OMe nBu 374 25Me H OMe nBu 388 26 Me H OH nBu 374 27 H H H OH 304 37 H H H OCF₃ 372 38H H H OiPr 346 39 Me H H OCF₃ 386 40 Me H H OiPr 360 41 H H H OH 304 42H OMe H OCF₃ 402 43 H OMe H OiPr 376 44 Me OMe H OCF₃ 416 45 Me OMe HOiPr 390 46 Me H H OnPr 360 47 Me OMe H OnPr 390

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

1. A compound of formula (I):

wherein A and B represent the groups —(CH₂)_(m)— and —(CH₂)_(n)—respectively; R¹ represents hydrogen or C₁₋₆alkyl; R² representshydrogen, halogen, hydroxy, cyano, nitro, hydroxyC₁₋₆alkyl,trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆fluoroalkoxy, —(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(p)OC₃₋₆cycloalkyl,—COC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl,—CO₂NR⁵R⁶, —SO₂NR⁵R⁶, —(CH₂)_(p)NR⁵R⁶, —(CH₂)_(p)NR⁵COR⁶,optionallysubstituted aryl ring, optionally substituted heteroaryl ring oroptionally substituted heterocyclyl ring; R³ represents hydrogen,halogen, hydroxy, cyano, nitro, hydroxyC₁₋₆alkyl, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆fluoroalkoxy,—(CH₂)_(p)C₃₋₆cycloalkyl, —(CH₂)_(p)OC₃₋₆cycloalkyl, —COC₁₋₆alkyl,—SO₂C₁₋₆alkyl, —SOC₁₋₆alkyl, —S—C₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂NR⁷R⁸,—SO₂NR⁷R⁸, —(CH₂)_(p)NR⁷R⁸ or —(CH₂)_(p)NR⁷COR⁸; R⁴ represents hydrogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆fluoroalkoxy, trifluoromethyl,trifluoromethoxy, halogen, —OSO₂CF₃, —(CH₂)_(p)C₃₋₆cycloalkyl,—(CH₂)_(q)OC₁₋₆alkyl or —(CH₂)_(p)OC₃₋₆cycloalkyl; R⁵ and R⁶ eachindependently represent hydrogen, C₁₋₆alkyl or, together with thenitrogen or other atoms to which they are attached, form anazacycloalkyl ring or an oxo-substituted azacycloalkyl ring; R⁷ and R⁸each independently represent hydrogen or C₁₋₆alkyl; m and nindependently represent an integer selected from 1 and 2; pindependently represents an integer selected from 0, 1, 2 and 3; qindependently represents an integer selected from 1, 2 and 3; or apharmaceutically acceptable salt or solvate thereof, with the provisothat the compounds8-hydroxy-3-methyl-7-phenylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine,8-hydroxy-7-(4-hydroxyphenyl)sulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine,7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline and7-phenylsulfonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride areexcluded.
 2. A compound of formula (I) according to claim 1 which is7-(4-n-butylphenylsulfonyl)-1,2,3,5-tetrahydro-3-benzazepine; or7-(4-n-butylphenylsulfonyl)-3-methyl-1,2,3,5-tetrahydro-3-benzazepine,and pharmaceutically acceptable solvates thereof.
 3. A pharmaceuticalcomposition comprising a compound of formula (I) as claimed in claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier therefor.
 4. A compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as claimed in claim1 for use in therapy.
 5. A method of treating a condition requiringmodulation of a dopamine receptor comprising administering a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof asclaimed in claim 1 to a mammal in need of such.
 6. A method of treatingpsychotic disorders, Parkinsons disease, substance abuse, dyskineticdisorders, depression, bipolar disorder, anxity and cognitive impairmentcomprising administering a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof as claimed in claim
 1. 7-8.(canceled)
 9. A method of treating a condition which requires modulationof a dopamine receptor, which comprises administering to a mammal inneed thereof an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as claimed inclaim
 1. 10. A method of treating psychotic disorders, Parkinsonsdisease, substance abuse, dyskinetic disorders, depression, bipolardisorder, anxiety, and cognitive impairment which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as claimed in claim 1.